1-Butanaminium, 4-hydroxy-N,N,N-trimethyl-4-oxo-, inner salt

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2000

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: study performed under GLP and in accordance with OECD-/EU-testing guidelines

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2000

Report date:

2000

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: Repeated Dose 28-day Oral Toxicity Study Regulation of Czech Ministry of Health No.251/1998 (identical with method B.7 Repeated dose (28 days) toxicity (oral) Directive 67/548/EEC)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Details on test material:

- Name of test material (as cited in study report): 4-Trimethylaminobutyrobetain
- Molecular formula: C7H1SN02
- Physical state: liquid
- Stability under test conditions: yes
- Storage condition of test material: at room temperature

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: TOP VELAZ, STO., závod Koleč
- Age at study initiation: 6 weeks
- Housing: group housing à 6 animals per sex and concentration
- Diet (e.g. ad libitum): Futtermittel-Mühle Kocanda, Jesenice u Prahy
- Water (e.g. ad libitum): tap water
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 30-70%
- Photoperiod (hrs dark / hrs light): 12 h darkness; 12 h continuous light

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

6 animals per sex and group were treated with the test item solution

Duration of treatment / exposure:

Test duration: 28 days

Frequency of treatment:

Daily

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0 mg/kg/day
Basis:
nominal in water

Doses / concentrations 2

Remarks:

Doses / Concentrations:
250 mg/kg/day
Basis:
nominal in water

Doses / concentrations 3

Remarks:

Doses / Concentrations:
500 mg/kg/day
Basis:
nominal in water

Doses / concentrations 4

Remarks:

Doses / Concentrations:
1000 mg/kg/day
Basis:
nominal in water

No. of animals per sex per dose:

MALES
- 6 animals: 0 mg/kg/day
- 6 animals: 250 mg/kg/day
- 6 animals: 500 mg/kg/day
- 6 animals: 1000 mg/kg/day

FEMALES
- 6 animals: 0 mg/kg/day
- 6 animals: 250 mg/kg/day
- 6 animals: 500 mg/kg/day
- 6 animals: 1000 mg/kg/day

Control animals:

yes

Positive control:

Control animals at 0 and 1000 mg/kg/day

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

The substance stimulates the general growth of animals (males and females). The substance increases the grip strength (only males, dose 250 mg/kg).

Mortality:

mortality observed, treatment-related

Description (incidence):

The substance stimulates the general growth of animals (males and females). The substance increases the grip strength (only males, dose 250 mg/kg).

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

no effects observed

Water consumption and compound intake (if drinking water study):

no effects observed

Ophthalmological findings:

no effects observed

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

See results section

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

Decreased levels: ALP (only males), creatinine; increased levels: potassium (only females).

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

See results section

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

See results sectio

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

HEMATOLOGY

1. Dose concentrations of 500 and 1000 mg/kg/day:
Damage of red blood components (both sex, irreversible processes):
- Decreased levels: Total number of red blood cells, the level of blood colour, hematokrit.
Damage of white blood components (both sex):
- Decreased levels: Total number of white blood cells, total amount of neutrofil segments.
- Decreased number of blood platelets (both sex, reversible process).

2. Dose concentration 250 mg/kg/day :
No substantial changes.


EFFECTS IN ORGANS

1. Dose concentrations of 500 and 1000 mg/kg/day:
- Decreased weight of thymus and increased weight of testes (reversible process). at 500 and 1000 mg/kg/day
- Increased steatosis of hepathocytes in males (reversible process). at 500 and 1000 mg/kg/day
- Desquamation of embryonal epithelium of testes (reversible process).
- Increased incidence of pigment in spleen of females (reversible process).
- Slight increase of areactive necrosis of villi apexis in small intestine.

2. Dose concentration 250 mg/kg/day:
- No substantial changes

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

250 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

2

Dose descriptor:

NOEL

Effect level:

< 250 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The NOAEL of the aqueous solution on WISTAR rats was found to be 250 mg/kg/day, whereas the NOEL was determined to be < 250 mg/kg/day.

Executive summary:

The test was performed 2000 under GLP according to the method Repeated Dose 28-day Oral Toxicity Study Regulation of Czech Ministry of Health No.251/1998 (identical with method B.7 Repeated dose (28 days) toxicity (oral) Directive 67/548/EEC). The study was performed on 6 male and 6 female Wistar rats at dose concentrations of 0, 250, 500 and 1000 mg/kg/day. There were neither mortality nor significant clinical symptoms observed. There were a couple of effects in hematological and biochemical parameters as well as some findings in organs at necropsy.